Developing a new drug for treating myocardial ischemia/reperfusion injury

开发治疗心肌缺血/再灌注损伤的新药

基本信息

批准号：
10491205
负责人：
Randal A Skidgel
金额：
$ 114.17万
依托单位：
DUPAGE MEDICAL TECHNOLOGY, INC.
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-09-20 至 2024-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10491205
关键词：
Acute Acute myocardial infarction Adverse effects Affect Animal Model Anti-Inflammatory Agents Antiinflammatory Effect Antiplatelet Drugs Arteries Aspirin Binding Blood Blood Platelets Blood Vessels Cardiac Cardiac Myocytes Cardiovascular Diseases Cause of Death Cells Clinical Treatment Coagulation Process Coronary artery Data Drug Delivery Systems Edema Effectiveness Extravasation Family suidae Fibrinolytic Agents Formulation GTP-Binding Proteins Heart Heart Diseases Heart failure Hemorrhage Hemostatic function Incidence Inflammation Inflammatory Inflammatory Response Integrins Intervention Intravenous Leukocytes Mediating Methods Molecular Morbidity - disease rate Myocardial Infarction Myocardial Ischemia Myocardial Reperfusion Nature Neutrophil Infiltration Operative Surgical Procedures Oral Outcome Patients Pattern Peptide Transport Peptides Pharmaceutical Preparations Phase Play Preparation Prevention Property Protein Subunits Reperfusion Injury Reperfusion Therapy Reporting Research Personnel Rodent Role Safety Science Secondary Prevention Signal Transduction Small Business Innovation Research Grant Stroke Survivors Therapeutic Effect Therapeutic Intervention Thrombolytic Therapy Thrombosis Time Tissues Toxic effect Toxicology Vascular blood supply acute toxicity antagonist base design drug production efficacy testing heart damage improved improved outcome in vivo inhibitor injury prevention method development mortality mouse model nanoparticle nanoparticle drug neutrophil novel novel therapeutics percutaneous coronary intervention porcine model preclinical study prevent scale up side effect stent thrombosis success theories thrombotic

项目摘要

Myocardial infarction (MI) is a prominent manifestation of heart disease with very high mortality. Despite the great success of surgical and intravascular interventions and thrombolytic therapies, MI mortality remains high and a significant percentage of MI survivors suffer from heart failure. Thus, there is a strong need and large market for new drugs to further reduce mortality and to treat post-MI heart failure. Treatment of MI requires timely reopening of the blocked coronary artery and reperfusion of the ischemic tissue. However, reperfusion itself may induce myocardial ischemia/reperfusion (MI/R) injury, which increases cardiac damage and mortality. It was shown that inflammation, consequent vascular leakage and microvascular thrombosis all play critical roles in MI/R injury. Anti-platelet drugs are routinely used in acute MI patients, mainly for the prevention of secondary thromboses or stent thrombosis. As microvascular thrombosis is a key factor in MI/R injury, anti- platelet drugs, in theory, should be protective. However, although anti-platelet treatment improves MI outcome in general, the more potent and fast-onset intravenous anti-platelet drugs, when used on top of mild and slow- acting oral anti-platelet drugs, are not significantly more effective in improving MI outcome than oral anti- platelet drugs alone. As the increased potency of the current anti-platelet drugs is associated with increased adverse effect of causing vascular leakage and bleeding, which are also important factors in MI/R injury, we hypothesize that these adverse effects may limit the efficacy of anti-platelet drugs in treating MI/R injury. Based on our new concept (Gong et al Science 2010, Shen et al, Nature 2013) that G13-dependent outside-in signaling of the platelet integrin IIb3 (GPIIb-IIIa) is selectively important in occlusive thrombosis but not hemostasis, we designed a peptide inhibitor of the G13-integrin interaction, M3mP6, and a novel high-loading peptide nanoparticle (HLPN) formulation for in vivo intracellular peptide delivery. In proof-of-concept studies, we have demonstrated that M3mP6 HLPN potently inhibits occlusive intravascular thrombosis without causing bleeding. Importantly, M3mP6 also has anti-inflammatory effects mediated by inhibition of 2-G13 binding in leukocytes, thereby reducing neutrophil function. M3mP6 had a striking therapeutic effect in treating MI/R injury in a mouse model. Pilot toxicology studies carried out with M3mP6 HLPN showed no toxicity. Based on these exciting new data, we propose in this direct Phase II SBIR application to further develop this novel drug from the proof-of-concept stage to IND for the treatment MI/R injury and prevention of post-MI heart failure. Our specific aims are (1) to compare the effect of M3mP6 HLPN to current standard anti-platelet therapy as well as their additive effects in treating MI/R injury and preventing post-MI heart failure in animal models. (2) to further evaluate the adverse effect of bleeding and toxicity of M3mP6 HLPN with and without current anti- platelet therapy. (3) Develop drug scale-up methods and prepare for IND submission. If successful, this new drug should have a major impact in further improving MI survival and reducing post-MI heart failure.

心肌梗塞（MI）是心脏病的一个突出表现，尽管死亡率非常高。手术、血管内干预和溶栓治疗取得巨大成功，心肌梗死死亡率仍然很高很大比例的心肌梗死幸存者患有心力衰竭，因此存在强烈的需求和巨大的需求。进一步降低死亡率和治疗 MI 后心力衰竭的新药市场。及时重新开通阻塞的冠状动脉并使缺血组织再灌注。其本身可能诱发心肌缺血/再灌注（MI/R）损伤，从而增加心脏损伤和死亡率。结果表明，炎症、随之而来的血管渗漏和微血管血栓形成都起着至关重要的作用抗血小板药物在急性 MI/R 损伤中的作用抗血小板药物常规用于急性 MI 患者，主要用于预防继发性血栓或支架内血栓形成由于微血管血栓是 MI/R 损伤的关键因素，因此抗理论上，血小板药物应该具有保护作用，但是，尽管抗血小板治疗可以改善心肌梗死的结局。一般来说，当在温和和缓慢的基础上使用时，更有效和快速起效的静脉注射抗血小板药物口服抗血小板药物在改善 MI 结局方面并不比口服抗血小板药物更有效由于当前抗血小板药物的效力增加与单独的血小板药物增加有关。引起血管渗漏和出血的不良反应也是MI/R损伤的重要因素，我们认为这些不良反应可能会限制抗血小板药物治疗 MI/R 损伤的疗效。根据我们的新概念（Gong 等人 Science 2010，Shen 等人，Nature 2013），G13 依赖于外向内血小板整合素 IIb3 (GPIIb-IIIa) 的信号传导在闭塞性血栓形成中选择性重要，但并非如此为了止血，我们设计了一种 Gα13-整合素相互作用的肽抑制剂 M3mP6 和一种新型高载量用于体内细胞内肽递送的肽纳米粒子（HLPN）制剂在概念验证研究中，我们已经证明 M3mP6 HLPN 有效抑制闭塞性血管内血栓形成，而不引起重要的是，M3mP6 还具有通过抑制 β2-Gα13 结合介导的抗炎作用。白细胞，从而降低中性粒细胞功能，M3mP6 在治疗 MI/R 中具有显着的治疗效果。使用 M3mP6 HLPN 进行的初步毒理学研究表明没有毒性。这些令人兴奋的新数据，我们建议在直接 II 期 SBIR 申请中进一步开发这种新药从治疗 MI/R 损伤和预防 MI 后心力衰竭的概念验证阶段到 IND。我们的具体目标是 (1) 将 M3mP6 HLPN 与当前标准抗血小板治疗的效果进行比较：以及它们在动物模型中治疗 MI/R 损伤和预防 MI 后心力衰竭的附加作用 (2) 至进一步评估M3mP6 HLPN在有或没有当前抗-治疗的情况下出血和毒性的不良影响 (3) 开发药物放大方法并为 IND 提交做好准备。该药物应该对进一步提高心肌梗死生存率和减少心肌梗死后心力衰竭产生重大影响。